Although recent advances in the treatment and monitoring of HIV-1 infection have substantially diminished HIV-associated illness and mortality, the management of HIV-infected patients has become increasingly complex. Both the acute and long-term toxicities of the common antiretroviral medications are becoming better understood and continue to complicate the successful management of this condition. Alternative treatment strategies are clearly needed, both for patients with access to HAART and, on a worldwide basis, particularly for the much greater number of patients with little or no access to these expensive therapies. Our clinical research continues to address several important aspects of the following questions: how to optimally dose anti-retroviral drugs; how to integrate immune based therapies within a framework of antiretroviral therapy; how to develop a successful antiretroviral strategy that employs periodic interruptions of treatment in order to spare drug and/or reduce toxicities, and how to optimize the use of immune-based therapies as a means of decreasing exposure to antiretroviral drugs. Studies employing interruptions of HAART on a serial basis have been undertaken in order to determine whether periodic intervals of treatment interruption may offer therapeutic equivalence to continuous therapy. Independent lines of evidence have now shown that the rate of peripheral lymphocyte turnover accelerates markedly upon withdrawal of antiretroviral therapy and returns to baseline levels shortly after re-introduction of HAART, strongly suggesting that viral activity directly influences the rate of CD4 proliferation. Virologic rebound is associated with a profound decrease in antigen responsiveness within the CD4 pool that recovers upon restoration of viral suppression. Another major focus of this project has been to characterize the immunologic abnormalities associated with HIV infection, develop immunologic approaches to the therapy of patients with HIV infection, and utilize these immune based therapies as tools for obtaining additional insights into the pathophysiologic mechanisms present in patients with HIV infection. Specifically, this project is aimed at reversing the CD4 cell decline associated with progressive HIV-1 infection through the use of subcutaneous administration of interleukin-2. A series of randomized phase I-II studies were carried out that established this as a feasible method for increasing the CD4 count in patients with HIV infection; these studies were then extended to optimize the dosing regimens for maximal immunologic and virologic benefit while minimizing side effects. Intensive efforts are underway to better characterize the function, replication, and survival of lymphocytes following both acute and chronic stimulation by IL-2 therapy. Cohorts of patients are being followed who have received IL-2 treatment for periods that now extend to almost 10 years. The laboratory has engaged in an extensive series of collaborations with a large number of extramural colleagues, both in the US and abroad, in the context of two major randomized phase III international clinical endpoint trials. The goal of these studies is to determine whether the favorable effects of IL-2 therapy on CD4 cell number translate into a significant delay in the onset of AID-defining conditions and/or death in recipients of IL-2 plus antiretrovirals versus patients on antiretoviral therapy alone. We have also served as lead center in a multi-center exploration of the safety and potential immunologic efficacy of an interleukin-2 analogue that has selectively enhanced binding affinity for the high-affinity IL-2 receptor and a more favorable toxicity profile in preclinical studies. Interleukin-2 (IL-2) is also being studied for its potential role in supplementing HAART therapy, specifically to determine whether it can be used as a HAART-sparing regimen for those who experience an initial CD4 cell increase from its use. We have initiated a randomized, controlled trial of scIL-2 with and without HAART interruption in an effort to determine how successful IL-2 therapy will be in eliminating the need for continuous HAART. We are also actively engaged in the design and implementation of similar exploratory studies of HAART-sparing strategies with extramural collaborators to address different facets of this issue. We have also performed phase I/II work with a novel CCR5 inhibitor compound and are engaged in subsequent phase II efforts to better characterize the activity, pharmacokinetics, and efficacy of this agent both alone and when added to a conventional HAART regimen. We also continue our efforts to improve access to clinical trials by local minority populations through an outreach that includes a close relationship with local clinics for the medically under-served. Finally, we have played an active role in helping establish a clinical research infrastructure in the South African National Defense Force military health-care system through our participation in the HIV research projects organized under Project Phidisa.